Rituximab (RTX) and Ofatumumab (OFA) efficacies in cancer therapy depend in part on the induction of complement-dependent cytotoxicity (CDC). Human CD59 (hCD59) is a key complement regulator that restricts the formation of membrane attack complex (MAC), thereby inhibiting induction of CDC. hCD59 is highly expressed in B-cell malignancies such as non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL) and up-regulation of hCD59 expression is an important determinant of the sensitivity of those cancer cells to RTX treatment. Therefore, it is imperative to develop a molecule capable of inhibiting hCD59 function in cancer cells and thus facilitate cancer immune therapy. However, targeted toxicity effect from antibody specific against hCD59 and less efficacy of C8 or C9 peptides limit them for therapeutic purposes. Recently, we have developed a specific and potent hCD59 inhibitor, ILYd4 (114AA), and demonstrated that 1) ILYd4 enhances CDC, thereby sensitizing RTX-resistant NHL cells and primary CLL to RTX or OFA treatment; 2) by itself ILYd4 does not adversely mediate in vivo hemolysis of hCD59-expressing erythrocytes; 3) the sensitivity to CDC effects mediated by RTX or OFA on RTX-resistant NHL cell lines and CLL cells negatively correlated with the level of CD59 on the cell surface; and 4) NHL cells overexpressing hCD59 were directly responsible for the resistance to RTX-mediated CDC. These results rationalize the use of ILYd4 as a lead biological candidate to develop a potential therapeutic adjuvant for RTX treatment of RTX-resistant NHL and CLL. Based on these results, we propose to develop marginally- or non- immunogenic, potent and stable ILYd4-derived peptides. We hypothesize that the optimized ILYd4-derived peptides will improve the physicochemical properties to enable parental administration, eliminate or reduce markedly immunogenicity, increase metabolic stability and half-life in circulation, and enhance therapeutic efficacy, thereby leading to effective ILYd4-related therapeutics that will function as an adjuvant to anti-cancer drugs such as OFA and RTX in B-cell malignancies that have relapsed after prior treatment with Ab-based therapies. Supportively, the availability of crystal structures of hCD59 and ILY enabled us to perform computational docking to identify potential interfaces between ILYd4 and hCD59 and predict nonfunctional and immunogenic epitopes. Recently, we generated a short form of ILYd4 by removing an immunogenic 21 AA residues in N-terminal region (ILYd4del21AA) and found that ILYd4del21AA had an anti-hCD59 activity at the level comparable to parental ILYd4. Therefore, we propose to develop active and deimmunized ILYd4del21AA and pegylate the deimmunized ILYd4del21AA, and to study the immunogenicity, the PK/PD, efficacy and toxicity profile in vivo. Successful outcome of this research will generate a novel therapeutic ILYd4 derivative for clinical trials that will test its efficacy as an adjuvantfor antibody-based cancer therapy such as RTX- or OFA-based B-cell malignancy therapy and provide the much needed means to overcome the devastating RTX- or OFA-resistant B-cell malignancies.